Crystalline forms of clazosentan sodium form i and form ii and methods of preparation

Abstract

The present application provides crystalline form I and crystalline form II of clazosentan sodium and a preparation method. The present application obtains new crystalline form I of clazosentan sodium with low residual solvent by using water as a solvent for recrystallization, and further obtains new crystalline form II by high-temperature beating, and the crystalline form has not been found so far, and the clazosentan sodium crystalline form I and crystalline form II prepared by the present application have low solvent residual amount, which is beneficial to improve product quality.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, and in particular relates to a crystalline form I and crystalline form II of clasenum sodium and a method for preparing them. Background Technology

[0002] Clazosentan sodium, chemically known as N-{6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-[2-(1H-tetrazol-5-yl)-pyridin-4-yl]-pyrimidin-4-yl}-amide disodium salt of 5-methyl-pyridine-2-sulfonic acid, is a selective endothelin receptor antagonist used to inhibit subarachnoid hemorrhage, intracranial vasospasm, and associated cerebral infarction and postoperative cerebral ischemia. Its structural formula is as follows:

[0003]

[0004] In existing technologies, the prepared clasentan sodium usually contains residual solvent, which affects product quality. Summary of the Invention

[0005] The purpose of this invention is to provide crystal form I and crystal form II of clasentan sodium and a preparation method thereof. Currently, no method has been found to prepare the two crystal forms described in this application. Furthermore, crystal form I and crystal form II of this invention have low solvent residue and the preparation method is simple.

[0006] The present invention provides a sodium clasenum crystal form I, wherein the X-ray powder diffraction pattern of sodium clasenum crystal form I has diffraction peaks at the following 2θ angles: 7.06°, 8.22°, 8.43°, 10.07°, 21.33°, 21.89°.

[0007] Preferably, the X-ray powder diffraction pattern of the clasenum sodium crystal form I is as follows: Figure 1 As shown.

[0008] This invention provides a method for preparing clasenum sodium crystal form I as described above, comprising the following steps:

[0009] Clarsentan sodium was mixed with water, heated to dissolve, then cooled to crystallize, filtered, and the solid was dried to obtain crystalline form I of clarsentan sodium.

[0010] The mass ratio of the clasenum sodium to the volume of water is 1 g: (2-20) mL.

[0011] Preferably, the temperature for heating and dissolving is 30–90°C.

[0012] Preferably, the cooling and crystallization temperature is 0–15°C.

[0013] This invention provides a sodium clasenum crystal form II, the X-ray powder diffraction pattern of which has diffraction peaks at the following 2θ angles: 8.44°, 10.13°, 11.24°, 12.43°, 13.19°, 14.86°, 16.88°, 17.15°, 19.83°, 20.62°, 21.13°, 22.25°, 22.66°, 25.62°.

[0014] Preferably, the X-ray powder diffraction pattern of the clasenum sodium crystal form II is as follows: Figure 2 As shown.

[0015] This invention provides a method for preparing clasenum sodium crystal form II as described above, comprising the following steps:

[0016] Clarsentan sodium crystal form I was refluxed in a solvent and pulped, then cooled and filtered. The filtered solid was dried to obtain clarsentan sodium crystal form II.

[0017] The solvent includes one or more of methanol, ethanol and isopropanol.

[0018] Preferably, the temperature of the reflux pulping is 50–100°C, and the reflux pulping time is 1–24 hours.

[0019] Preferably, the cooling temperature is -10 to 20°C.

[0020] This invention obtains a new crystal form I, clasentan sodium, with low residual solvent by recrystallization using water as a solvent, and further obtains a new crystal form II by high-temperature pulping. No other preparation of this crystal form has been found to date. Moreover, the clasentan sodium crystal forms I and II prepared by this invention have low residual solvent content, which is beneficial to improving product quality. Attached Figure Description

[0021] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on the provided drawings without creative effort.

[0022] Figure 1 This is the powder X-ray diffraction pattern of sodium clasenum crystal form I in Example 1 of the present invention;

[0023] Figure 2 This is a powder X-ray diffraction pattern of sodium clasenum crystal form II in Example 2 of the present invention. Detailed Implementation

[0024] The present invention provides a sodium clasenum crystal form I, wherein the X-ray powder diffraction pattern of sodium clasenum crystal form I has diffraction peaks at the following 2θ angles: 7.06°, 8.22°, 8.43°, 10.07°, 21.33°, 21.89°.

[0025] This invention also provides a method for preparing the above-described clasenum sodium crystal form I, comprising the following steps:

[0026] Clarsentan sodium was mixed with water, heated to dissolve, then cooled to crystallize, filtered, and the solid was dried to obtain crystalline form I of clarsentan sodium.

[0027] The mass ratio of the clasenum sodium to the volume of water is 1 g: (2-20) mL.

[0028] In this invention, the source of the clasentan sodium is not particularly limited; it can be prepared by conventional methods in the art or commercially available clasentan sodium can be used directly. The water is preferably purified water.

[0029] In this invention, the mass ratio of clasentan sodium to water volume is preferably 1g:(2-20)mL, more preferably 1g:(5-15)mL, such as 1g:2mL, 1g:3mL, 1g:4mL, 1g:5mL, 1g:6mL, 1g:7mL, 1g:8mL, 1g:9mL, 1g:10mL, 1g:11mL, 1g:12mL, 1g:13mL, 1g:14mL, 1g:15mL, 1g:16mL, 1g:17mL, 1g:18mL, 1g:19mL, 1g:20mL, preferably within the range of any of the above values ​​as the upper or lower limit.

[0030] In this invention, the temperature for heating and dissolving is preferably 30-90°C, more preferably 40-80°C, such as 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, 90°C, and preferably any of the above values ​​as the upper or lower limit; there is no special limitation on the time for heating and dissolving, as long as it can completely dissolve and obtain a clear solution.

[0031] In this invention, the cooling and crystallization temperature is preferably 0 to 20°C, more preferably 0 to 15°C, such as 0°C, 1°C, 2°C, 3°C, 4°C, 5°C, 6°C, 7°C, 8°C, 9°C, 10°C, 11°C, 12°C, 13°C, 14°C, 15°C, preferably a range of values ​​with any of the above values ​​as the upper or lower limit; the cooling and crystallization time is not particularly limited, until no crystals precipitate.

[0032] After cooling and crystallization, the present invention filters the crystals, and the resulting filter cake is dried to obtain sodium clasenum crystal form I.

[0033] In this invention, the drying is preferably carried out in a vacuum drying oven, preferably under reduced pressure, and the drying temperature is preferably 60-80°C, more preferably 70-75°C; the drying time is preferably 1-24 hours, more preferably 12-18 hours. The vacuum degree of the drying is preferably -0.085 to -0.099 MPa.

[0034] This invention provides a sodium clasenum crystal form II, the X-ray powder diffraction pattern of which has diffraction peaks at the following 2θ angles: 8.44°, 10.13°, 11.24°, 12.43°, 13.19°, 14.86°, 16.88°, 17.15°, 19.83°, 20.62°, 21.13°, 22.25°, 22.66°, 25.62°.

[0035] This invention also provides a method for preparing clasenum sodium crystal form II, comprising the following steps:

[0036] Clarsentan sodium crystal form I was refluxed in a solvent and pulped, then cooled and filtered. The filtered solid was dried to obtain clarsentan sodium crystal form II.

[0037] The solvent includes one or more of methanol, ethanol and isopropanol.

[0038] In this invention, the clasentan sodium crystal form I is the clasentan sodium crystal form I described above or the clasentan sodium crystal form I prepared by the preparation method described above.

[0039] In this invention, the temperature of the reflux pulping is preferably 50-100℃, more preferably 60-90℃, such as 50℃, 60℃, 70℃, 80℃, 90℃, 100℃, preferably a range of values ​​with the above values ​​as the upper or lower limit; the time of the reflux pulping is preferably 1-24 hours, more preferably 2-5 hours.

[0040] In this invention, the cooling temperature is preferably -10 to 20°C, more preferably -5 to 15°C, such as -10°C, -9°C, -8°C, -7°C, -6°C, -5°C, -4°C, -3°C, -2°C, -1°C, 0°C, 1°C, 2°C, 3°C, 4°C, 5°C, 6°C, 7°C, 8°C, 9°C, 10°C, 11°C, 12°C, 13°C, 14°C, 15°C, 16°C, 17°C, 18°C, 19°C, 20°C, preferably a range of values ​​with any of the above values ​​as the upper or lower limit; the cooling time is not particularly limited, until no crystals precipitate.

[0041] In this invention, the drying is preferably carried out in a vacuum drying oven, preferably under reduced pressure, and the drying temperature is preferably 60-80°C, more preferably 70-75°C; the drying time is preferably 1-24 hours, more preferably 12-18 hours. The vacuum degree of the drying is preferably -0.085 to -0.099 MPa.

[0042] To further illustrate the present invention, the following detailed description of a clasenum sodium crystal form I and crystal form II and its preparation method provided by the present invention is provided in conjunction with embodiments, but it should not be construed as limiting the scope of protection of the present invention.

[0043] Example 1

[0044] 10.0 g of clasentan sodium and 40 ml of purified water were added sequentially to a reaction flask. The mixture was heated to 75 ± 2 °C to dissolve completely. After dissolution, the temperature was lowered to 2 ± 2 °C and stirred for 6 hours. The mixture was filtered, and the filter cake was dried under reduced pressure at 70 °C to obtain 9.1 g of clasentan sodium in its new crystal form I. No residual solvents of ethanol or methanol were detected, and the moisture content was 3.7%. Its powder X-ray diffraction pattern is shown below. Figure 1 As shown, Figure 1 Peaks are observed at the following refraction angles of 2θ (values ​​in parentheses are diffraction intensities): 7.06° (100%), 8.22° (10.86%), 8.43° (10.21%), 10.07° (19.13%), 21.33° (16.84%), and 21.89° (12.80%).

[0045] Example 2

[0046] 5.0 g of clasentan sodium crystal form I and 80 ml of ethanol were added sequentially to a reaction flask. The mixture was heated to 80 ± 2 °C and stirred under reflux for 12 h, then cooled to -7 ± 2 °C and stirred for 2 h. The mixture was filtered, and the filter cake was dried under reduced pressure at 70 °C to obtain 4.7 g of clasentan sodium crystal form II. The residual solvent was 850 ppm ethanol, and the water content was 1.9%. Its powder X-ray diffraction pattern is shown below. Figure 2 As shown, Figure 2 Peaks are shown at the following refraction angles of 2θ (values ​​in parentheses are diffraction intensities): 8.44° (100%), 10.13° (79.70%), 11.24° (13.14%), 12.43° (12.71%), 13.19° (10.31%), 14.86° (12.45%), 16.88° (24.70%), 17.15° (11.13%), 19.83° (29.54%), 20.62° (22.63%), 21.13° (13.09%), 22.25° (17.60%), 22.66° (12.84%), and 25.62° (25.79%).

[0047] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A sodium clasenum crystal form I, wherein the X-ray powder diffraction pattern of sodium clasenum crystal form I has diffraction peaks at the following 2θ angles: 7.06°, 8.22°, 8.43°, 10.07°, 21.33°, 21.89°.

2. The sodium clasenum crystal form I according to claim 1, characterized in that, The X-ray powder diffraction pattern of the sodium clasenum crystal form I is shown in Figure 1.

3. A method for preparing clasenum sodium crystal form I as described in claim 1 or 2, comprising the following steps: Clarsentan sodium was mixed with water, heated to dissolve, then cooled to crystallize, filtered, and the solid was dried to obtain crystalline form I of clarsentan sodium. The mass ratio of the clasenum sodium to the volume of water is 1 g: (2-20) mL.

4. The preparation method according to claim 3, characterized in that, The temperature for heating and dissolving is 30–90°C.

5. The preparation method according to claim 3, characterized in that, The cooling and crystallization temperature is 0–15°C.

6. A sodium clasenum crystal form II, wherein the X-ray powder diffraction pattern of the sodium clasenum crystal form II has diffraction peaks at the following 2θ angles: 8.44°, 10.13°, 11.24°, 12.43°, 13.19°, 14.86°, 16.88°, 17.15°, 19.83°, 20.62°, 21.13°, 22.25°, 22.66°, 25.62°.

7. The sodium clasenum crystal form II according to claim 6, characterized in that, The X-ray powder diffraction pattern of the sodium clasenum crystal form II is shown in Figure 2.

8. A method for preparing clasenum sodium crystal form II as described in claim 6 or 7, comprising the following steps: Clarsentan sodium crystal form I was refluxed in a solvent and pulped, then cooled and filtered. The filtered solid was dried to obtain clarsentan sodium crystal form II. The solvent includes one or more of methanol, ethanol and isopropanol.

9. The preparation method according to claim 8, characterized in that, The temperature of the reflux pulping is 50–100°C, and the reflux pulping time is 1–24 hours.

10. The preparation method according to claim 8, characterized in that, The cooling temperature is -10 to 20°C.

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